Sex shapes the systemic response to light-induced sleep disruption in Drosophila melanogaster.

Light is the fundamental Zeitgeber aligning sleep and circadian physiology. Here, we rigorously challenged this system by exposing male and female Drosophila melanogaster to constant light (LL) or fragmented photoperiods (4I, 8I), modeling chronic circadian disruption. All protocols markedly reduced sleep quantity and stability, with females exhibiting pronounced vulnerability in sleep consolidation and locomotor control. Metabolic profiling revealed glucose and lipid disturbances, increased ROS levels, and altered SOD and CAT activity. Mitochondrial assessments revealed sex-specific deficits, with higher proton leak and diminished respiratory efficiency in females, whereas males maintained relative resilience, except under severe fragmentation. Thermal stress further exposed reduced resilience, especially in 8I-exposed flies. These data establish sex as a pivotal determinant of susceptibility to environmental circadian misalignment, integrating behavioral, metabolic, oxidative, and bioenergetic layers. Our work provides a comprehensive framework to dissect sex-dependent vulnerabilities to light-induced circadian disruption, with broad implications for understanding sleep and metabolic disorders.